Benzoic acid, benzoic acid derivatives and heteroaryl carboxylic acid conjugates of hydrocodone, prodrugs, methods of making and use thereof

ABSTRACT

The presently described technology provides methods of treating a patient having moderate to severe pain, narcotic or opioid abuse or narcotic or opioid withdrawal. The presently described methods are carried out by comprising administering to the patient a pharmaceutically effective amount of a composition comprising acetaminophen and benzoate-hydrocodone hydrochloride. The composition has reduced side effects when compared with unconjugated hydrocodone.

RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.14/816,915, filed Aug. 3, 2015, which is a continuation-in-part of U.S.application Ser. No. 14/557,570, filed Dec. 2, 2014, which is acontinuation of U.S. application Ser. No. 13/888,587, filed May 7, 2013,which is a continuation of U.S. application Ser. No. 12/828,381, filedJul. 1, 2010, now U.S. Pat. No. 8,461,137, which claims priority to andbenefit of U.S. provisional patent application No. 61/222,718, filedJul. 2, 2009, all of which are herein incorporated by reference in theirentireties.

FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[Not Applicable]

BACKGROUND OF THE INVENTION

Opioids are highly effective as analgesics and are commonly prescribedfor the treatment of acute and chronic pain. They are also commonly usedas antitussives. The opioids, however, also produce euphoria and arehighly addictive. As a result they are often abused with far reachingsocial and health related consequences.

Because of the inherent potential for abuse, it is desirable that anypharmaceutical composition containing an opioid agonist be made asabuse-resistant or abuse-deterrent as practical. Illicit users oftenwill attempt to circumvent the extended release properties of thesedosage forms by injecting or otherwise misusing the product in order toachieve an immediate release of the opioid agonist.

Despite their addictive properties and the potential for abuse,morphine-like drugs, particularly, codeine, hydrocodone, and oxycodonehave been routinely prescribed as treatment for severe acute and chronicpain in recent decades. This is, in part, because there are noalternatives to relieve severe pain that is resistant to other lesspotent analgesics such as non-steroidal anti-inflammatory drugs(NSAIDS). In this regard, there is a need to decrease the abusepotential. Thus far, approaches taken, unfortunately, have not solvedthe problem.

Hydrocodone is an opioid analgesic and antitussive and occurs as fine,white crystals or as crystalline powder. Hydrocodone is a semisyntheticnarcotic analgesic prepared from codeine with multiple actionsqualitatively similar to those of codeine. It is mainly used for reliefof moderate to moderately severe pain. Additionally, it is used as anantitussive in cough syrups and tablets in sub-analgesic doses (2.5-5mg).

Patients taking opioid analgesics such as hydrocodone for pain reliefcan become unintentionally addicted. As tolerance to the opioidsdevelops more drug is needed to alleviate the pain and generate thesense of wellbeing initially achieved with the prescribed dose. Thisleads to dose escalation, which if left unchecked can lead rapidly toaddiction. In some cases patients have become very addicted in as littleas thirty days.

BRIEF SUMMARY OF THE INVENTION

The present technology utilizes covalent conjugation of the opioidhydrocodone with certain aryl carboxylic acids to decrease its potentialfor causing overdose or abuse by requiring the active hydrocodone to bereleased through enzymatic or metabolic breakdown of the conjugate invivo. The present technology also provides methods of deliveringhydrocodone as conjugates that release the hydrocodone following oraladministration while being resistant to abuse by circuitous routes suchas intravenous (“shooting”) injection and intranasal administration(“snorting”).

The presently described technology in at least one aspect provides aslow/sustained/controlled release composition of conjugated hydrocodonethat allows slow/sustained/controlled delivery of the hydrocodone and/orits active metabolite, hydromorphone, into the blood system of a humanor animal within a safe therapeutic window upon, for example, oraladministration. At least some compositions/formulations of the currenttechnology can lessen addiction/abuse potential and/or other common sideeffects associated with hydrocodone and similar compounds.

In one aspect, the present technology provides a composition comprisingat least one conjugate of hydrocodone and at least one benzoic acid orderivative thereof, a salt thereof, or a combination thereof, thebenzoic acid or derivative thereof having the following formula I:

where X, Y and Z are independently selected from the group consisting ofH, O, S, NH and —(CH₂)_(x)—; R¹, R² and R³ are independently selectedfrom the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl,halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy,cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are independentlyselected from 0 or 1; and x is an integer between 1 and 10. In someaspects, the benzoic acid or derivative thereof is an amino benzoate, ahydroxybenzoate, an aminohydroxybenzoate, a derivative thereof, orcombination thereof.

In another aspect, the present technology provides a compositioncomprising at least one conjugate of hydrocodone and at least onebenzoic acid, a derivative thereof, or a combination thereof.

In yet another aspect, the present technology provides conjugates ofhydrocodone for use to treat pain, preferably moderate to severe pain,or for use to reduce or prevent oral, intranasal or intravenous drugabuse. In some aspects, the conjugates provide oral, intranasal orparenteral drug abuse resistance.

In another aspect, the present technology provides at least oneconjugate of hydrocodone that exhibits a slower rate of release overtime and a greater or equal AUC when compared to an equivalent molaramount of unconjugated hydrocodone over the same time period. In otheraspects, the conjugate of hydrocodone exhibits less variability in theoral PK profile when compared to unconjugated hydrocodone. In yetanother aspect, at least one conjugate has reduced side effects whencompared with unconjugated hydrocodone or prevents drug tampering byeither physical or chemical manipulation.

In another aspect, at least one conjugate is provided in an amountsufficient to provide a therapeutically bioequivalent AUC when comparedto an equivalent molar amount of unconjugated hydrocodone. In furtheraspects, at least one conjugate is provided in an amount sufficient toprovide a therapeutically bioequivalent AUC when compared to anequivalent molar amount of unconjugated hydrocodone but does not providea C_(max) spike or has a lower C_(max) than a therapeutically equivalentamount of unconjugated hydrocodone. In yet a further aspect, at leastone conjugate is provided in an amount sufficient to provide atherapeutically bioequivalent AUC when compared to an equivalent molaramount of unconjugated hydrocodone, but does not provide an equivalentC_(max) spike. In some aspects, at least one conjugate provides anequivalent C_(max) spike when compared to unconjugated hydrocodone.

In yet another aspect, the present technology provides a method fortreating a patient having a disease, disorder or condition requiring ormediated by binding of an opioid to the opioid receptors of the patient,comprising orally administering to the patient a pharmaceuticallyeffective amount of at least one conjugate of hydrocodone and at leastone benzoic acid or derivative thereof, a salt thereof, or a combinationthereof, the benzoic acid or derivative thereof having formula I:

where X, Y and Z are independently selected from the group consisting ofH, O, S, NH and —(CH₂)_(x)—; R¹, R² and R³ are independently selectedfrom the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl,halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy,cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are independentlyselected from 0 or 1; and x is an integer between 1 and 10.

In another aspect, at least one conjugate binds irreversibly to theopioid receptors of the patient. In yet another aspect, at least oneconjugate binds irreversibly to the opioid receptors of the patientwithout a CNS depressive effect.

In a further aspect, the present technology provides a method fortreating a patient having a disease, disorder or condition requiring ormediated by inhibiting binding of an opioid to the opioid receptors ofthe patient, comprising orally administering to the patient apharmaceutically effective amount of at least one conjugate ofhydrocodone and at least one benzoic acid or derivative thereof, a saltthereof, or a combination thereof, the benzoic acid or derivativethereof having formula I:

wherein

X, Y and Z are independently selected from the group consisting of H, O,S, NH and —(CH₂)_(x)—; R¹, R² and R³ are independently selected from thegroup consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl, halo,haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy, cycloalkyl,cycloalkenyl and cycloalkynyl; o, p, q are independently selected from 0or 1; and x is an integer between 1 and 10.

In some aspects, the present technology provides at least one conjugatethat reversibly inhibits binding of an opioid to the opioid receptor ofthe patient. In other aspects, at least one conjugate reversiblyinhibits binding of an opioid to the opioid receptor of the patientwithout a CNS depressive effect.

In a further aspect, the present technology provides a method fortreating a patient having a disease, disorder or condition (such aspain) which can be treated by binding of an opioid to the opioidreceptors of the patient, the method comprising orally administering tothe patient a pharmaceutically effective amount of at least oneconjugate of hydrocodone and at least one benzoic acid, a salt thereof,a derivative thereof or a combination thereof.

In another aspect, the present technology provides a method for treatinga patient having a disease, disorder or condition (such as addiction)which can be treated by inhibiting binding of an opioid to the opioidreceptors of the patient, comprising orally administering to the patienta pharmaceutically effective amount of at least one conjugate ofhydrocodone and at least one benzoic acid, a salt thereof, a derivativethereof or a combination thereof.

In yet another aspect, the present technology provides a pharmaceuticalkit including a specified amount of individual doses in a packagecontaining a pharmaceutically effective amount of at least one conjugateof hydrocodone and at least one benzoate, a salt thereof, a derivativethereof or a combination thereof, the benzoate having the formula I:

wherein X, Y and Z are independently selected from the group consistingof H, O, S, NH and —(CH₂)_(x)—; R¹, R² and R³ are independently selectedfrom the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl,halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy,cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q can be independentlyselected from 0 or 1; and x is an integer between 1 and 10. In someaspects, the kit further comprises instructions for use of the kit in amethod for treating or preventing drug withdrawal symptoms or pain in ahuman or animal patient.

In another aspect, the present technology provides a pharmaceutical kitincluding a specified amount of individual doses in a package containinga pharmaceutically effective amount of at least one conjugate ofhydrocodone and at least one benzoic acid, a salt thereof, a derivativethereof or a combination thereof. In some aspects, the kit furtherincludes instructions for use of the kit in a method for treating orpreventing drug withdrawal symptoms or pain in a human or animalpatient.

In yet another aspect, the present technology provides a compositioncomprising at least one conjugate of hydrocodone and at least oneheteroaryl carboxylic acid, a derivative thereof, or a combinationthereof.

In yet another aspect, the present technology provides at least oneconjugate of hydrocodone and at least one heteroaryl carboxylic acid, aderivative thereof, or a combination thereof where at least oneheteroaryl carboxylic acid is selected from formula II, formula III orformula IV, wherein formula II, formula III and formula IV are:

wherein X, Y and Z are independently selected from the group consistingof H, O, S, NH and —(CH₂)_(x)—; R¹, R² and R³ are independently selectedfrom the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl,halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy,cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are independentlyselected from 0 or 1; and x is an integer from 1 to 10. In some aspects,at least one heteroaryl carboxylic acid is a pyridine derivative.

In some aspects, the present technology provides at least one conjugatethat prevents drug tampering by either physical or chemicalmanipulation.

In another aspect, the present technology provides a method for treatinga patient having a disease, disorder or condition requiring or mediatedby binding of an opioid to the opioid receptors of the patient,comprising orally administering to the patient a pharmaceuticallyeffective amount of at least one conjugate of hydrocodone and at leastone heteroaryl carboxylic acid.

In a further aspect, the present technology provides a method fortreating a patient having a disease, disorder or condition requiring ormediated by binding of an opioid to the opioid receptors of the patient,comprising orally administering to the patient a pharmaceuticallyeffective amount of at least one conjugate of hydrocodone and at leastone heteroaryl carboxylic acid, where the heteroaryl carboxylic acid isselected from formula II, formula III or formula IV, wherein formula II,formula III and formula IV are:

where X, Y and Z are independently selected from the group consisting ofH, O, S, NH and —(CH₂)_(x)—; R¹, R² and R³ are independently selectedfrom the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl,halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy,cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are independentlyselected from 0 or 1; and x is an integer from 1 to 10.

In another aspect, the present technology provides a method for treatinga patient having a disease, disorder or condition requiring or mediatedby binding of an opioid to the opioid receptors of the patient,comprising orally administering to the patient a pharmaceuticallyeffective amount of at least one conjugate of hydrocodone and at leastone nicotinic acid, a derivative thereof, or a combination thereof.

In another aspect, the present technology provides a method for treatinga patient having a disease, disorder or condition requiring or mediatedby inhibiting binding of an opioid to the opioid receptors of thepatient, comprising orally administering to the patient apharmaceutically effective amount of at least one conjugate ofhydrocodone and at least one heteroaryl carboxylic acid. In someaspects, the heteroaryl carboxylic acid is selected from formula II,formula III or formula IV, wherein formula II, formula III and formulaIV are:

wherein X, Y and Z are independently selected from the group consistingof H, O, S, NH and —(CH₂)_(x)—; R¹, R² and R³ are independently selectedfrom the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl,halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy,cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are independentlyselected from 0 or 1; and x is an integer from 1 to 10.

In another aspect, the present technology provides a method for treatinga patient having a disease, disorder or condition requiring or mediatedby inhibiting binding of an opioid to the opioid receptors of thepatient, comprising orally administering to the patient apharmaceutically effective amount of at least one conjugate ofhydrocodone and at least one nicotinic acid, a derivative thereof, or acombination thereof.

In yet another aspect, the present technology provides a pharmaceuticalkit including a specified number of individual doses in a packagecontaining a pharmaceutically effective amount of at least one conjugateof hydrocodone and at least one heteroaryl carboxylic acid, a derivativethereof, or a combination thereof, wherein the heteroaryl carboxylicacid is selected from formula II, formula III or formula IV, whereinformula II, formula III and formula IV are:

wherein X, Y and Z are independently selected from the group consistingof H, O, S, NH and —(CH₂)_(x)—; R¹, R² and R³ are independently selectedfrom the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl,halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy,cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are independentlyselected from 0 or 1; and x is an integer from 1 to 10. In some aspects,the kit further comprises instructions for use of the kit in a methodfor treating or preventing drug withdrawal symptoms or pain in a humanor animal patient.

In yet another aspect, the present technology provides a prodrugcomprising at least one conjugate of hydrocodone and at least onebenzoic acid or benzoic acid derivative, a salt thereof, or acombination thereof, the benzoic acid or benzoic acid derivative havingthe following formula I:

where X, Y and Z are independently selected from the group consisting ofH, O, S, NH and —(CH₂)_(x)—; R¹, R² and R³ are independently selectedfrom the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl,halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy,cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are independentlyselected from 0 or 1; and x is an integer between 1 and 10.

In another aspect, the present technology provides a prodrug comprisingat least one conjugate of hydrocodone and at least one benzoic acid, aderivative thereof, or a combination thereof.

In yet another aspect, the present technology provides a prodrugcomprising at least one conjugate of hydrocodone and at least oneheteroaryl carboxylic acid, a derivative thereof, or a combinationthereof. In some aspects, the prodrug includes at least one heteroarylcarboxylic acid selected from formula II, formula III or formula IV,wherein formula II, formula III and formula IV are:

wherein X, Y and Z are independently selected from the group consistingof H, O, S, NH and —(CH₂)_(x)—; R¹, R² and R³ are independently selectedfrom the group consisting of H, alkyl, alkoxy, aryl, alkenyl, alkynyl,halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy,cycloalkyl, cycloalkenyl and cycloalkynyl; o, p, q are independentlyselected from 0 or 1; and x is an integer from 1 to 10.

In yet another aspect, the present technology provides a prodrugcomprising at least one conjugate of hydrocodone and at least onenicotinic acid, a derivative thereof, or a combination thereof.

In some aspects, the prodrug includes an amino benzoate, ahydroxybenzoate, an aminohydroxybenzoate, a derivative thereof, orcombination thereof.

In some aspects, at least one conjugate binds reversibly to the opioidreceptors of the patient. In some further aspects, at least oneconjugate binds reversibly to the opioid receptors of the patientwithout a CNS depressive effect. In yet another aspect, at least oneconjugate prevents or reduces at least one constipatory side effect ofunconjugated hydrocodone.

In one aspect, the present technology provides a method for treating apatient having moderate to severe pain, narcotic or opioid abuse; ornarcotic or opioid withdrawal. The method may be carried out byadministering to the patient a pharmaceutically effective amount of acomposition comprising acetaminophen and benzoate-hydrocodonehydrochloride. The composition has reduced side effects when comparedwith unconjugated hydrocodone.

In another aspect, the present technology provides a method for treatinga patient having moderate to severe pain, narcotic or opioid abuse; ornarcotic or opioid withdrawal comprising administering to the patient apharmaceutically effective amount of a composition of a conjugate ofhydrocodone wherein the conjugate exhibits lower mean exposure tohydrocodone about more than 53 mg when compared to unconjugatedhydrocodone; or has reduced side effects when compared with anequivalent molar amount of unconjugated hydrocodone.

Optionally in any embodiment, the composition may comprisebenzoate-hydrocodone hydrochloride and acetaminophen having a molarratio from 0.001:1 to 1000:1. Optionally in any embodiment, thecomposition may be conjugate or a prodrug.

Optionally in any embodiment, the composition may be used to reduce orprevent oral, intranasal or intravenous drug abuse; or to provide oral,intranasal or parenteral drug abuse resistance. Optionally in anyembodiment, the composition may exhibit an improved AUC and rate ofrelease of hydrocodone over time when compared to unconjugatedhydrocodone over the same time period; exhibits lower exposure tohydrocodone at about more than 53 mg when compared to an equivalentmolar amount of unconjugated hydrocodone.

Optionally in any embodiment, the composition may exhibit an improvedAUC and rate of release of hydromorphone over time when compared tounconjugated hydrocodone over the same time period; exhibits lowerexposure to hydromorphone at about more than 53 mg when compared to anequivalent molar amount of unconjugated hydrocodone.

Optionally in any embodiment, the composition may exhibit a lowermaximum peak exposure (C_(max)) to hydrocodone at about more than 53 mgwhen compared to an equivalent molar amount of unconjugated hydrocodone.

Optionally in any embodiment, the composition may exhibit a lowermaximum peak exposure (C_(max)) to hydromorphone at about more than 53mg when compared to an equivalent molar amount of unconjugatedhydrocodone.

Optionally in any embodiment, the composition may be provided in adosage form selected from the group consisting of: a tablet, a capsule,a caplet, a suppository, a troche, a lozenge, an oral powder, asolution, an oral film, a thin strip, a slurry, and a suspension.

Optionally in any embodiment, the composition may be provided in anamount sufficient to provide a therapeutically bioequivalent AUC forhydrocodone at about lower than 53 mg when compared to an equivalentmolar amount of unconjugated hydrocodone.

Optionally in any embodiment, at least one composition may be providedin an amount sufficient to provide a therapeutically bioequivalent AUCand C_(max) for hydrocodone at about lower than 53 mg when compared toan equivalent molar amount of unconjugated hydrocodone.

Optionally in any embodiment, one of the reduced side effects comprisesa lower than normal concentration of oxygen in arterial blood of thepatient (hypoxia).

Optionally in any embodiment, one of the reduced side effects comprisesrespiratory depression in the patient.

BRIEF DESCRIPTION OF SEVERAL VIEWS OF THE DRAWINGS

FIG. 1. Chemical structures of hydroxybenzoic acids and benzoic acidderivatives for use in the making of the conjugates of the presenttechnology.

FIG. 2. Chemical structures of aminobenzoic acids for use in the makingof the conjugates of the present technology.

FIG. 3. Chemical structures of aminohydroxybenzoic acids for use in themaking of conjugates of the present technology.

FIG. 4. FIG. 4A is a Table of common hydrocodone products and dosageranges and FIG. 4B is a Table of common hydrocodone products used incough syrups.

FIG. 5. PK profile graph of plasma concentrations of hydrocodonereleased from Bz-HC (benzoate-hydrocodone), YYFFI-HC(Tyr-Tyr-Phe-Phe-Ile-Hydrocodone) and Diglycolate-HC over time upon oraladministration in rats.

FIG. 6. PK profile graph of plasma concentrations of active metabolitehydromorphone over time upon oral administration of Bz-HC, YYFFI-HC, andDiglycolate-HC in rats.

FIG. 7. PK profile graph of plasma concentrations of hydrocodonereleased from Bz-HC and Adipate-HC over time upon intranasaladministration in rats.

FIG. 8. PK profile graph of plasma concentrations of active metabolitehydromorphone over time upon intranasal administration of Bz-HC andAdipate-HC in rats.

FIG. 9. PK profile graph of plasma concentrations of hydrocodonereleased from Bz-HC, Nicotinate-HC and Hydrocodone.BT over time uponoral administration in rats.

FIG. 10. PK profile graph of plasma concentrations of active metabolitehydromorphone over time upon oral administration of Bz-HC, Nicotinate-HCand Hydrocodone.BT in rats.

FIG. 11. PK profile graph of plasma concentrations of hydrocodonereleased from Bz-HC, 2-ABz-HC and Hydrocodone.BT over time upon oraladministration in rats.

FIG. 12. PK profile graph of plasma concentrations of active metabolitehydromorphone over time upon oral administration of Bz-HC, 2-ABz-HC andHydrocodone.BT in rats.

FIG. 13. Synthesis diagrams of conjugates of hydrocodone.

FIG. 13A depicts the synthesis of benzoate hydrocodone. FIG. 13B depictsthe synthesis of nicotinate hydrocodone (nicotinic acid). FIG. 13Cdepicts the synthesis of 2-aminobenzoate hydrocodone. FIG. 13D depictsthe synthesis of salicylate hydrocodone.

FIG. 14. PK profile graph of plasma concentrations of intact Bz-HC,active metabolite hydromorphone and of hydrocodone released from Bz-HCover time upon oral administration in rats.

FIG. 15. PK profile graph of plasma concentrations of hydrocodonereleased from Bz-HC and hydrocodone.BT over time upon oraladministration in dogs.

FIG. 16. PK profile graph of plasma concentrations of active metabolitehydromorphone over time upon oral administration of Bz-HC andhydrocodone.BT in dogs.

FIG. 17. PK profile graph of plasma concentrations of intact Bz-HC andof hydrocodone released from Bz-HC over time upon oral administration indogs.

FIG. 18. PK profile graph of plasma concentrations of intact Bz-HC,active metabolite hydromorphone and of hydrocodone released from Bz-HCover time upon intravenous administration in rats at 0.30 mg/kg.

FIG. 19. PK profile graph of plasma concentrations of hydrocodonereleased from Bz-HC over time upon oral administration in rats at sixdifferent dosages.

FIG. 20. PK profile graph of plasma concentrations of active metabolitehydromorphone over time upon oral administration of Bz-HC in rats at sixdifferent dosages.

FIG. 21a . PK profile graph of plasma concentrations of hydrocodonereleased from Bz HC.HCl/APAP (6.67 mg/325 mg) and HB/APAP over acomplete time course upon oral administration of three single doses inrecreational drug users.

FIG. 21b . PK profile graph of plasma concentrations of hydrocodonereleased from Bz-HC.HCl/APAP (6.67 mg/325 mg) and HB/APAP over a first 3hours of post-dose upon oral administration of three single doses inrecreational drug users.

FIG. 22a . PK profile graph of plasma concentrations of hydromorphonereleased from Bz-HC.HCl/APAP (6.67 mg/325 mg) and HB/APAP over acomplete time course upon oral administration of three single doses inrecreational drug users.

FIG. 22b . PK profile graph of plasma concentrations of hydromorphonereleased from Bz-HC.HCl/APAP (6.67 mg/325 mg) and HB/APAP over a first 3hours of post-dose upon oral administration of three single doses inrecreational drug users.

DETAILED DESCRIPTION OF THE INVENTION

The present technology provides compositions comprising aryl carboxylicacids chemically conjugated to hydrocodone (morphinan-6-one,4,5-alpha-epoxy-3-methoxy-17-methyl) to form novel prodrugs andcompositions of hydrocodone. In some embodiments, the chemical bondbetween these two moieties can be established by reacting the C-6 enoltautomer of hydrocodone with the activated carboxylic acid function ofan aryl carboxylic acid thereby creating an enol-ester conjugate.

The use of “opioid” is meant to include any drug that activates theopioid receptors found in the brain, spinal cord and gut. There are fourbroad classes of opioids: naturally occurring opium alkaloids, such asmorphine (the prototypical opioid) codeine, and thebaine; endogenousopioid peptides, such as endorphins; semi-synthetics such as heroine,oxycodone and hydrocodone that are produced by modifying natural opiumalkaloids (opiates) and have similar chemical structures; and puresynthetics such as fentanyl and methadone that are not produced fromopium and may have very different chemical structures than the opiumalkaloids. Additional examples of opioids are hydromorphone,oxymorphone, methadone, levorphanol, dihydrocodeine, meperidine,diphenoxylate, sufentanil, alfentanil, propoxyphene, pentazocine,nalbuphine, butorphanol, buprenorphine, meptazinol, dezocine, andpharmaceutically acceptable salts thereof.

The use of “hydrocodone” is meant to include a semisynthetic narcoticanalgesic and antitussive prepared from codeine with multiple actionsqualitatively similar to those of codeine. It is commonly used for therelief of moderate to moderately severe pain. Trade names includeAnexsia™, Hycodan™, Hycomine™, Lorcet™, Lortab™, Norco™, Tussionex™,Tylox™, and Vicodin™. Other salt forms of hydrocodone, such ashydrocodone bitartrate and hydrocodone polistirex, are encompassed bythe present technology.

The use of “prodrug” is meant to include pharmacologically inactivesubstances that are a modified form of a pharmacologically active drugto which it is converted in the body by, for example, enzymatic action,such as during first pass metabolism.

As used herein, the following conventional unit abbreviations and termsare used as follows: “pg” refers to picogram, “ng” refers to nanogram,“μg” refers to microgram, “mg” refers to milligram, “g” refers to gram,“kg” refers to kilogram, “mL” refers to milliliter, “h” refers to hourand “t” refers to time.

As used herein, the following conventional pharmacokinetic abbreviationsand terms are used as follows: “PK” refers to pharmacokinetics,“AUC_(0-t)” refers to area under the plasma concentration-time curve tothe last time with a concentration ≥LLOQ, “AUC_(int)” refers to the areaunder the plasma concentration-time curve to infinity, “C_(max)” refersto the maximum plasma concentration, “T_(max)” refers to the time ofmaximum plasma concentration, and “t_(1/2)” refers to the eliminationhalf-life.

As used herein, the following conventional statistical abbreviations andterms are used as follows: “LLOQ” refers to the validated lower limit ofthe bioanalytical method, “ANOVA” refers to Analysis of Variance and “p”refers to probability.

As used herein, “APAP” refers to acetaminophen.

As used herein, “LC/MS/MS” refers to liquid chromatography/massspectrometry/mass spectrometry.

Some embodiments of the present technology provide carboxylic acidsconjugated to hydrocodone, where the carboxylic acid group is directlyattached to the aryl moiety. Carboxylic acids directly attached to thearyl moiety include benzoates and heteroaryl carboxylic acids.

Some embodiments of the present technology provide at least oneconjugate of hydrocodone and at least one benzoic acid or benzoic acidderivative, a salt thereof, or a combination thereof. Benzoates arecommon in nature and include, for example but are not limited to,aminobenzoates (e.g., anthranilic acid analogs such as fenamates),aminohydroxybenzoates and hydroxybenzoates (e.g., salicylic acidanalogs).

The general structure of benzoic acid and benzoic acid derivatives ofthe present technology is:

where X, Y and Z can be independently any combination of H, O, S, NH or—(CH₂)—; R¹, R² and R³ can be independently any of the following: H,alkyl, alkoxy, aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl,arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl orcycloalkynyl, and o, p, q can be independently either 0 or 1.

Suitable hydroxyobenzoic acids can be found in FIG. 1 and include, butare not limited to, benzoic acid, salicylic acid, acetylsalicylic acid(aspirin), 3-hydroxybenzoic acid, 4-hydroxybenzoic acid,6-methylsalicylic acid, o,m,p-cresotinic acid, anacardic acids,4,5-dimethylsalicylic acid, o,m,p-thymotic acid, diflusinal,o,m,p-anisic acid, 2,3-dihydroxybenzoic acid (2,3-DHB), α,β,γ-resorcylicacid, protocatechuic acid, gentisic acid, piperonylic acid,3-methoxysalicylic acid, 4-methoxysalicylic acid, 5-methoxysalicylicacid, 6-methoxysalicylic acid, 3-hydroxy-2-methoxybenzoic acid,4-hydroxy-2-methoxybenzoic acid, 5-hydroxy-2-methoxybenzoic acid,vanillic acid, isovanillic acid, 5-hydroxy-3-methoxybenzoic acid,2,3-dimethoxybenzoic acid, 2,4-dimethoxybenzoic acid,2,5-dimethoxybenzoic acid, 2,6-dimethoxybenzoic acid, veratric acid(3,4-dimethoxybenzoic acid), 3,5-dimethoxybenzoic acid, gallic acid,2,3,4-trihydroxybenzoic acid, 2,3,6-trihydroxybenzoic acid,2,4,5-trihydroxybenzoic acid, 3-O-methylgallic acid (3-OMGA),4-O-methylgallic acid (4-OMGA), 3,4-O-dimethylgallic acid, syringicacid, 3,4,5-trimethoxybenzoic acid.

Suitable aminobenzoic acids are shown in FIG. 2 and include, but are notlimited to, anthranilic acid, 3-aminobenzoic acid,4,5-dimethylanthranilic acid, N-methylanthranilic acid,N-acetylanthranilic acid, fenamic acids (e.g., tolfenamic acid,mefenamic acid, flufenamic acid), 2,4-diaminobenzoic acid (2,4-DABA),2-acetylamino-4-aminobenzoic acid, 4-acetylamino-2-aminobenzoic acid,2,4-diacetylaminobenzoic acid.

Suitable aminohydroxybenzoic acids include, but are not limited to,4-Aminosalicylic acid, 3-hydroxyanthranilic acid, 3-methoxyanthranilicacid.

In some embodiments, the composition includes a benzoate conjugatecomprising at least one hydrocodone conjugated to at least one benzoicacid or benzoic acid derivative, salt thereof or combination thereof.

In some embodiments, the benzoates include numerous benzoic acidanalogs, benzoate derivatives with hydroxyl or amino groups or acombination of both. The hydroxyl and amino functions may be present intheir free form or capped with another chemical moiety, preferably butnot limited to methyl or acetyl groups. The phenyl ring may haveadditional substituents, but the total number of substituents can befour or less, three or less, or two or less.

In another embodiment, the prodrug or conjugate composition of thepresent technology is benzoate-hydrocodone, which has the structure:

In yet another embodiment, the present technology provides a prodrug orcomposition comprising at least one conjugate of hydrocodone and atleast one heteroaryl carboxylic acid, a derivative thereof, or acombination thereof. The heteroaryl carboxylic acid can be selected fromformula II, formula III or formula IV where formula II, formula III andformula IV are:

For these formulas, X, Y and Z are independently selected from the groupconsisting of H, O, S, NH and —(CH₂)_(x)—; R¹, R² and R³ areindependently selected from the group consisting of H, alkyl, alkoxy,aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl, arylalkyl,heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl; o,p, q are independently selected from 0 or 1; and x is an integer from 1to 10.

In some embodiments, the carboxy group of the aryl carboxylic acids canbe attached directly to the aromatic ring. The present technologyincludes both carbon-only aryl groups and aryl groups with heteroatoms(heteroaryl). The aryl or heteroaryl group which is connected directlyto the carboxyl function can be a 6-membered ring and contains no or oneheteroatom. In some embodiments, the additional substituted orunsubstituted aromatic or aliphatic rings can be fused to this6-membered aryl or heteroaryl moiety. In some embodiments, the arylcarboxylic acids may have only one free carboxylic acid group and thetotal number of phenyl substituents on the 6-membered ring should befour or less, for example, 4, 3, 2 or 1.

In some embodiments of the present technology, depending on theindividual aryl carboxylic acid that is connected to hydrocodone, theconjugate of hydrocodone can have a neutral, free acid, free base, orvarious pharmaceutically acceptable anionic or cationic salt forms orsalt mixtures with any ratio between positive and negative components.These salt forms include, but are not limited to: acetate, L-aspartate,besylate, bicarbonate, carbonate, D-camsylate, L-camsylate, citrate,edisylate, fumarate, gluconate, hydrobromide/bromide,hydrochloride/chloride, D-lactate, L-lactate, D,L-lactate, D,L-malate,L-malate, mesylate, pamoate, phosphate, succinate, sulfate, D-tartrate,L-tartrate, D,L-tartrate, meso-tartrate, benzoate, gluceptate,D-glucuronate, hybenzate, isethionate, malonate, methylsulfate,2-napsylate, nicotinate, nitrate, orotate, stearate, tosylate,acefyllinate, aceturate, aminosalicylate, ascorbate, borate, butyrate,camphorate, camphocarbonate, decanoate, hexanoate, cholate, cypionate,dichloroacetate, edentate, ethyl sulfate, furate, fusidate, galactarate(mucate), galacturonate, gallate, gentisate, glutamate, glutarate,glycerophosphate, heptanoate (enanthate), hydroxybenzoate, hippurate,phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate,mandelate, methanesulfonate, myristate, napadisilate, oleate, oxalate,palmitate, picrate, pivalate, propionate, pyrophosphate, salicylate,salicylsulfate, sulfosalicylate, tannate, terephthalate, thiosalicylate,tribrophenate, valerate, valproate, adipate, 4-acetamidobenzoate,camsylate, octanoate, estolate, esylate, glycolate, thiocyanate, andundecylenate.

For the present technology, a suitable conjugate of hydrocodone includesnicotinate-hydrocodone, which has the following structure:

Some embodiments of the present technology provide a conjugate ofhydrocodone that is broken down in vivo either enzymatically orotherwise, releasing the active hydrocodone and the respective arylcarboxylic acid or metabolites thereof. The aryl carboxylic acids usedin the conjugates of the present technology are non-toxic at the givendosing levels and are preferably known drugs, natural products,metabolites, or GRAS (Generally Regarded As Safe) compounds (e.g.,preservatives, dyes, flavors, etc.) or non-toxic mimetics thereof.

Compounds, compositions and methods of the present technology providereduced potential for overdose, reduced potential for abuse or addictionand/or improve hydrocodone's characteristics with regard to hightoxicities or suboptimal release profiles. Without wishing to be limitedto the below theory, the present inventors believe that overdoseprotection may occur due to the conjugates being exposed to differentenzymes and/or metabolic pathways by oral administration where theconjugate is exposed through the gut and first-pass metabolism asopposed to exposure to enzymes in the circulation or mucosal membraneswhich limits the ability of the hydrocodone from being released from theconjugate. Therefore, abuse resistance is provided by limiting the“rush” or “high” available from the active hydrocodone released by theprodrug and limiting the effectiveness of alternative routes ofadministration.

The compositions of the present technology preferably have no or asubstantially decreased pharmacological activity when administeredthrough injection or intranasal routes of administration. However, theyremain orally bioavailable. Again, not wanting to be bound by anyparticular theory, the bioavailability can be a result of the hydrolysisof the chemical linkage (i.e., a covalent linkage) following oraladministration. In at least one embodiment, release of hydrocodone isreduced when the composition of the present technology is delivered byparenteral routes.

For example, in one embodiment, the composition of the presenttechnology maintains its effectiveness and abuse resistance followingthe crushing of the tablet, capsule or other oral dosage form. Incontrast, from parental non-conjugated (or “unconjugated”) forms ofhydrocodone, the hydrocodone is released immediately following crushingallowing the content of the crushed tablet to be used by injection orsnorting producing the “rush” effect sought by addicts.

In some embodiments of the present technology, the conjugates ofhydrocodone can be given orally to an animal or human patient, and, uponadministration, release the active hydrocodone by being hydrolyzed inthe body. Not to be bound by any particular theory, it is believed thatsince the aryl carboxylic acids are naturally occurring metabolites ormimetics thereof or pharmaceutically active compounds, these conjugatescan be easily recognized by physiological systems resulting inhydrolysis and release of hydrocodone. The conjugates themselves haveeither no or limited pharmacological activity as a conjugate andconsequently may follow a metabolic pathway that differs from the parentdrug.

In some embodiments of the present technology, the choice of a suitablearyl carboxylic acids (“ligands”) to conjugate to hydrocodone determinesthe release of hydrocodone into the systemic circulation and can becontrolled even when the conjugate is administered via routes other thanoral. In one embodiment, the modified hydrocodone would releasehydrocodone similar to free or unmodified hydrocodone. In anotherembodiment, the conjugated hydrocodone releases hydrocodone in acontrolled or sustained form. In some embodiments, this controlledrelease can alleviate certain side-effects and improve upon the safetyprofile of the parent drug. These side-effects may include, but are notlimited to, anxiety, bruising, constipation, decreased appetite,difficulty breathing, dizziness, drowsiness, dry throat, diarrhea,headache, nausea, stomach cramps, stomach pain, vomiting. In anotherembodiment, the conjugated hydrocodone would selectively allowhydrocodone to be metabolized to hydromorphone. In some embodiments,these conjugates can be used for pain relief, such as moderate to severepain relief.

Hydrocodone and other opioids are also highly addictive and prone tosubstance abuse. Recreational drug abuse of opioids is a common problemand usually begins with oral doses taken with the purpose of achievingeuphoria (“rush”, “high”). Over time the drug abuser often increases theoral dosages to attain more powerful “highs” or to compensate forheightened opioid tolerance. This behavior can escalate and result inexploring of other routes of administration such as intranasal(“snorting”) and intravenous (“shooting”).

In some embodiments of the present technology, the hydrocodone that isconjugated with a suitable aryl carboxylic acid ligand does not resultin rapid spikes in plasma concentrations after oral administration thatis sought by a potential drug abuser. In some embodiments, hydrocodonereleased from these conjugates has a delayed T_(max) and possibly lowerC_(max) than the unconjugated hydrocodone. Not to be bound by anyparticular theory, it is believed that the conjugates of the presenttechnology, when taken orally or by other non-oral routes, do notprovide the feeling of a “rush” even when taken at higher doses butstill maintain pain relief.

Additionally, in some embodiments, hydrocodone conjugated withappropriate ligands of the present technology is not hydrolyzedefficiently when administered via non-oral routes. As a result, theseconjugates do not generate high plasma or blood concentrations ofreleased hydrocodone when injected or snorted compared to freehydrocodone administered through these routes.

In some embodiments, the conjugates of the present technology, sincethey consist of covalently bound hydrocodone, are not able to bephysically manipulated to release the hydrocodone opioid from theconjugated hydrocodone by methods, for example, of grinding up orcrushing of solid forms. Further, the conjugates of the presenttechnology exhibits resistance to chemical hydrolysis under conditions apotential drug abuser may apply to “extract” the active portion of themolecule, for example, by boiling, or acidic or basic solution treatmentof the conjugate.

The compositions and prodrugs of the present technology can be oraldosage forms. These dosage forms include but are not limited to tablet,capsule, caplet, troche, lozenge, powder, suspension, syrup, solution ororal thin film (OTF). Preferred oral administration forms are capsule,tablet, solutions and OTF.

Solid dosage forms can include, but are not limited to, the followingtypes of excipients: antiadherents, binders, coatings, disintegrants,fillers, flavors and colors, glidants, lubricants, preservatives,sorbents and sweeteners.

Oral formulations of the present technology can also be included in asolution or a suspension in an aqueous liquid or a non-aqueous liquid.The formulation can be an emulsion, such as an oil-in-water liquidemulsion or a water-in-oil liquid emulsion. The oils can be administeredby adding the purified and sterilized liquids to a prepared enteralformula, which is then placed in the feeding tube of a patient who isunable to swallow.

Soft gel or soft gelatin capsules may be prepared, for example bydispersing the formulation in an appropriate vehicle (vegetable oils arecommonly used) to form a high viscosity mixture. This mixture is thenencapsulated with a gelatin based film using technology and machineryknown to those in the soft gel industry. The individual units so formedare then dried to constant weight.

Chewable tablets, for example, may be prepared by mixing theformulations with excipients designed to form a relatively soft,flavored, tablet dosage form that is intended to be chewed rather thanswallowed. Conventional tablet machinery and procedures, for example,direct compression and granulation, i.e., or slugging, beforecompression, can be utilized. Those individuals involved inpharmaceutical solid dosage form production are versed in the processesand the machinery used, as the chewable dosage form is a very commondosage form in the pharmaceutical industry.

Film coated tablets, for example may be prepared by coating tabletsusing techniques such as rotating pan coating methods or air suspensionmethods to deposit a contiguous film layer on a tablet.

Compressed tablets, for example may be prepared by mixing theformulation with excipients intended to add binding qualities todisintegration qualities. The mixture is either directly compressed orgranulated then compressed using methods and machinery known to those inthe industry. The resultant compressed tablet dosage units are thenpackaged according to market need, for example, in unit dose, rolls,bulk bottles, blister packs, etc.

The present technology also contemplates the use ofbiologically-acceptable carriers which may be prepared from a wide rangeof materials. Without being limited to, such materials include diluents,binders and adhesives, lubricants, plasticizers, disintegrants,colorants, bulking substances, flavorings, sweeteners and miscellaneousmaterials such as buffers and adsorbents in order to prepare aparticular medicated composition.

Binders may be selected from a wide range of materials such ashydroxypropylmethylcellulose, ethylcellulose, or other suitablecellulose derivatives, povidone, acrylic and methacrylic acidco-polymers, pharmaceutical glaze, gums, milk derivatives, such as whey,starches, and derivatives, as well as other conventional binders knownto persons working in the art. Exemplary non-limiting solvents arewater, ethanol, isopropyl alcohol, methylene chloride or mixtures andcombinations thereof. Exemplary non-limiting bulking substances includesugar, lactose, gelatin, starch, and silicon dioxide.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations of the present technology can includeother suitable agents such as flavoring agents, preservatives andantioxidants. Such antioxidants would be food acceptable and couldinclude vitamin E, carotene, BHT or other antioxidants.

Other compounds which may be included by admixture are, for example,medically inert ingredients, e.g., solid and liquid diluents, such aslactose, dextrose, saccharose, cellulose, starch or calcium phosphatefor tablets or capsules, olive oil or ethyl oleate for soft capsules andwater or vegetable oil for suspensions or emulsions; lubricating agentssuch as silica, talc, stearic acid, magnesium or calcium stearate and/orpolyethylene glycols; gelling agents such as colloidal clays; thickeningagents such as gum tragacanth or sodium alginate, binding agents such asstarches, arabic gums, gelatin, methylcellulose, carboxymethylcelluloseor polyvinylpyrrolidone; disintegrating agents such as starch, alginicacid, alginates or sodium starch glycolate; effervescing mixtures;dyestuff; sweeteners; wetting agents such as lecithin, polysorbates orlaurylsulfates; and other therapeutically acceptable accessoryingredients, such as humectants, preservatives, buffers andantioxidants, which are known additives for such formulations.

For oral administration, fine powders or granules containing diluting,dispersing and/or surface-active agents may be presented in a draught,in water or a syrup, in capsules or sachets in the dry state, in anon-aqueous suspension wherein suspending agents may be included, or ina suspension in water or a syrup. Where desirable, flavoring,preserving, suspending, thickening or emulsifying agents can beincluded.

Liquid dispersions for oral administration may be syrups, emulsions orsuspensions. The syrups may contain as carrier, for example, saccharoseor saccharose with glycerol and/or mannitol and/or sorbitol. Inparticular a syrup for diabetic patients can contain as carriers onlyproducts, for example sorbitol, which do not metabolize to glucose orwhich metabolize only a very small amount to glucose. The suspensionsand the emulsions may contain a carrier, for example a natural gum,agar, sodium alginate, pectin, methylcellulose, carboxymethylcelluloseor polyvinyl alcohol.

Current approved formulations of hydrocodone are combination therapiesof hydrocodone and one or more other non-narcotic active ingredientdepending on intended indication. Examples of these activepharmaceuticals include, but are not limited to, acetaminophen,phenylpropanolamine, homatropine, ibuprofen, aspirin, pheniramine,chlorpheniramine, phenylephrine, pseudoephedrine, pyrilamine andguaifenesin. The conjugated hydrocodone of the present technology can beformulated with one or a combination of these or other active substancesor as standalone active ingredient without any other actives.

Certain formulations of the compounds, products, compositions,conjugates and prodrugs of the current technology comprise Bz-HC.HCl,bulking agents and diluents, such as, for example, microcrystallinecellulose and crospovidone, disintegrants, such as, for example, starch1500 G, binders, such as, for example, povidone K30, lubricants, suchas, for example, stearic acid, and granulation solvents, such as, forexample, purified water. Such formulations of the current technology mayalso include additional pharmaceutical actives, such as, for example,acetaminophen.

The amounts and relative percentages of the different active andinactive components of the formulations of the current technology can bemodified, selected and adjusted in order to arrive at desirableformulations, dosages and dosage forms for therapeutic administration ofthe compounds, products, compositions, conjugates and prodrugs of thecurrent technology. One such oral dosage formulation of the presenttechnology is presented, for example, in Table 1.

TABLE 1 Strength (label claim) 6.67 mg/325 mg Component and Quality(Bz-HC•HCl/ Standard (and Grade, if Acetaminophen) applicable) Functionmg/tablet % w/w Bz-HC•HCl^(a,) Professed Active 6.67 1.21 AcetaminophenUSP Active 325.0 59.09 Microcrystalline Bulking Agent 154.78 28.16Cellulose NF Crospovidone NF Bulking 16.0 2.9 Agent/Diluent Starch 1500G NF Disintegrant 20.0 3.64 Povidone K30 NF Binder 23.65 4.3 StearicAcid NF Lubricant 3.9 0.71 Purified water^(a) Granulation n/a n/asolvent ^(a)Removed by evaporation during the process.

The conjugate compositions or prodrugs may be used in methods oftreating a patient having a disease, disorder or condition requiring ormediated by binding or inhibiting binding of an opioid to the opioidreceptors of the patient. Treatment comprises orally administering tothe patient a pharmaceutically effective amount of at least oneconjugate of hydrocodone as described in the present technology. Theconjugate can exhibit a slower rate of release over time and AUC whencompared to an equivalent molar amount of unconjugated hydrocodone. Inother embodiments, at least one conjugate can exhibit less variabilityin the oral PK profile when compared to unconjugated hydrocodone.

In other embodiments, at least one conjugate is provided in an amountsufficient to provide a therapeutically bioequivalent AUC (area underthe curve) when compared to a molar equivalent amount of unconjugatedhydrocodone. In further embodiments, the conjugate is provided in anamount sufficient to provide a therapeutically bioequivalent AUC whencompared to unconjugated hydrocodone but has a lower C_(max) (peakconcentration) in plasma or does not provide an equivalent C_(max) inplasma concentrations. In some aspects, the conjugate is provided in anamount sufficient to provide a therapeutically bioequivalent C_(max)when compared to unconjugated hydrocodone.

Suitable diseases, disorders or conditions that can be treated by theprodrugs or compositions of the present technology are narcoticaddiction or drug addiction and/or acute or chronic pain.

Dosages for the conjugates of the present technology depend on theirmolecular weight and the respective weight-percentage of hydrocodone aspart of the whole conjugate, and therefore can be higher than thedosages of free hydrocodone. Dosages can be calculated based on thestrengths of dosages of hydrocodone bitartrate which range between 2.5mg and 15 mg per dose. Dose conversion from hydrocodone bitartrate tohydrocodone prodrug can be performed using the following formula:

dose(HC prodrug/conjugate)=[dose(HC bitartrate)×(molecular weight(HCprodrug/conjugate)/494.49)]/proportion of hydrocodone released fromprodrug/conjugate

HC: hydrocodone

Suitable dosages of the conjugated hydrocodone of the present technologyinclude, but are not limited to, formulations including from about 0.5mg or higher, alternatively from about 2.5 mg or higher, alternativelyfrom about 5.0 mg or higher, alternatively from about 7.5 mg or higher,alternatively from about 10 mg or higher, alternatively from about 20 mgor higher, alternatively from about 30 mg or higher, alternatively fromabout 40 mg or higher, alternatively from about 50 mg or higher,alternatively from about 60 mg or higher, alternatively from about 70 mgor higher, alternatively from about 80 mg or higher, alternatively fromabout 90 mg or higher, alternatively from about 100 mg or higher, andinclude any additional increments thereof, for example, 0.1, 0.2, 0.25,0.3, 0.4, 0.5, 0.6, 0.7, 0.75, 0.8, 0.9 or 1.0 mg and multiplied factorsthereof, (e.g., ×1, ×2, ×2.5, ×5, ×10, ×100, etc). The presenttechnology also includes dosage formulations including currentlyapproved formulations of hydrocodone (See FIG. 4), where the dosage canbe calculated using the above-noted formula determined by the amount ofhydrocodone bitartrate. The present technology provides for dosage formsformulated as a single therapy or as a combination therapy with otherAPI's (FIG. 4).

The conjugates of hydrocodone with derivatives of benzoic acid ornicotinic acid of the present technology have a number of advantagesincluding, but not limited to, a reduced patient variability of plasmaconcentrations of hydrocodone or hydromorphone when compared to freehydrocodone, reduced drug abuse potential, reduced risk of chemical orphysical manipulation resulting in full dosage of hydrocodone released,improved dosage forms through covalent linkage to carboxylic acids orderivatives thereof, increased or decreased metabolism of hydrocodone tohydromorphone and/or decreased side-effects other than drug abuse.

Hydrocodone is a narcotic analgesic, which acts as weak agonist atopioid receptors in the central nervous system (CNS). It primarilyaffects the μ (mu) receptor (OP3), but also exhibits agonist activity atthe δ (delta) receptor (OP1) and κ (kappa) receptor (OP2). Additionally,hydrocodone displays antitussive properties by suppressing the coughreflex in the medullary cough center of the brain.

Side effects of opioid analgesics include gastrointestinal dysfunctioncaused by the opioids binding to the mu (μ) receptors present in thegastrointestinal tract. The side-effects in the stomach include areduction in the secretion of hydrochloric acid, decreased gastricmotility, thus prolonging gastric emptying time, which can result inesophageal reflux. Passage of the gastric contents through the duodenummay be delayed by as much as 12 hours, and the absorption of orallyadministered drugs is retarded. In the small intestines the opioidanalgesics diminish biliary, pancreatic and intestinal secretions anddelay digestion of food in the small intestine. Propulsive peristalticwaves in the colon are diminished or abolished after administration ofopioids, and tone is increased to the point of spasm. The resultingdelay in the passage of bowel contents causes considerable desiccationof the feces, which, in turn retards their advance through the colon.These actions, combined with inattention to the normal sensory stimulifor defecation reflex due to the central actions of the drug, contributeto opioid-induced constipation.

Hydrocodone is used for the treatment of moderate to moderately severepain and for inhibition of cough (especially dry, nonproductive cough).The prodrugs of the present technology may be administered for therelief of pain or cough depression or for the treatment of any conditionthat may require the blocking of opioid receptors.

The conjugates of the present technology can provide a decrease in sideeffects of the opioid analgesic, including reduced or inhibitedconstipatory effects.

The present technology also provides a method of synthesis for thepreparation of the conjugated hydrocodone of the present technology. Inone embodiment, the synthesis of the present technology includes thesteps of:

-   -   1. Protection of the ligand, if necessary;    -   2. Activation of the ligand carboxylic acid group, if not        already in activated form;    -   3. Addition of the activated ligand to hydrocodone or vice versa        in the presence of base; and    -   4. Removal of ligand protecting groups, if applicable.

If the aryl carboxylic acid contains any additional reactive functionalgroups that may interfere with the coupling to hydrocodone, it may benecessary to first attach one or more protecting groups. Any suitableprotecting group may be used depending on the type of functional groupand reaction conditions. Some protecting group examples are: acetyl(Ac), β-methoxyethoxymethyl ether (MEM), methoxymethyl ether (MOM),p-methoxybenzyl ether (PMB), trimethylsilyl (TMS),tert.-butyldimethylsilyl (TBDPS), triisopropylsilyl (TIPS),carbobenzyloxy (Cbz), p-methoxybenzyl carbonyl (Moz),tert.-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc),benzyl (Bn), p-methoxybenzyl (MPM), tosyl (Ts). Temporary formation ofacetals or ketals from carbonyl functions may also be appropriate.

The carboxylic acid group of the ligands should be activated in order toreact with hydrocodone and to generate appreciable amounts of conjugate.This activation can be accomplished in numerous ways by a variety ofcoupling agents known to one skilled in the art. Examples of suchcoupling agents are: N,N-dicyclohexylcarbodiimide (DCC),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDCl),N,N′-diisopropylcarbodiimide (DIC), 1,1′-carbonyldiimidazole (CDl) orother carbodiimides;(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(BOP), bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP),(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate(PyBOP) or other phosphonium-based reagents;O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TBTU), fluoro-N,N,N′,N′-tetramethylformamidiniumhexafluorophosphate (TFFH),N,N,N′,N′-tetramethyl-O—(N-succinimidyl)uronium tetrafluoroborate (TSTU)or other aminium-based reagents. The aryl carboxylic acid can also beconverted to a suitable acyl halide, acyl azide or mixed anhydride.

A base may be required at any step in the synthetic scheme of an arylcarboxylic acid conjugate of hydrocodone. Suitable bases include but arenot limited to: 4-methylmorpholine (NMM), 4-(dimethylamino)pyridine(DMAP), N,N-diisopropylethylamine, lithium bis(trimethylsilyl)amide,lithium diisopropylamide (LDA), any alkali metal tert.-butoxide (e.g.,potassium tert.-butoxide), any alkali metal hydride (e.g., sodiumhydride), any alkali metal alkoxide (e.g., sodium methoxide),triethylamine or any other tertiary amine.

Suitable solvents that can be used for any reaction in the syntheticscheme of an aryl carboxylic acid conjugate of hydrocodone include butare not limited to: acetone, acetonitrile, butanol, chloroform,dichloromethane, dimethylformamide (DMF), dimethylsulfoxide (DMSO),dioxane, ethanol, ethyl acetate, diethyl ether, heptane, hexane,methanol, methyl tert.-butyl ether (MTBE), isopropanol, isopropylacetate, diisopropyl ether, tetrahydrofuran, toluene, xylene or water.

In some embodiments, the prodrug is hydrophobic and thus poorly watersoluble. This results in a gel-like consistency or clumpy suspensionwhen the compound is mixed with water. Examples of these prodrugsinclude, but are not limited to, Piperonylate-HC, 3-OH-4-MeO-Bz-HC,3-OH-Bz-HC and Gallate-HC. These prodrugs cannot be dosed intranasallyin rats due to their lack of water solubility. Not to be bound by anytheory, it is assumed that these compounds would also congeal or becomeclumpy when a human subject tries to inhale them intranasally(“snorting”). This property would not only make an attempt of intranasalabuse an unpleasant experience but would likely also prevent the prodrugfrom permeating the nose mucosa. As a consequence, these compoundsbecome ineffective for this route of administration.

The present technology provides pharmaceutical kits for the treatment orprevention of drug withdrawal symptoms or pain in a patient. The patientmay be a human or animal patient. Suitable human patients includepediatric patients, geriatric (elderly) patients, and normativepatients. The kit comprises a specific amount of the individual doses ina package containing a pharmaceutically effective amount of at least oneconjugate of hydrocodone of the present technology. The kit can furtherinclude instructions for use of the kit. The specified amount ofindividual doses may contain from about 1 to about 100 individualdosages, alternatively from about 1 to about 60 individual dosages,alternatively from about 10 to about 30 individual dosages, including,about 1, about 2, about 5, about 10, about 15, about 20, about 25, about30, about 35, about 40, about 45, about 50, about 55, about 60, about70, about 80, about 100, and include any additional increments thereof,for example, 1, 2, 5, 10 and multiplied factors thereof, (e.g., ×1, ×2,×2.5, ×5, ×10, ×100, etc).

The presently described technology and its advantages will be betterunderstood by reference to the following examples. These examples areprovided to describe specific embodiments of the present technology. Byproviding these specific examples, it is not intended limit the scopeand spirit of the present technology. It will be understood by thoseskilled in the art that the full scope of the presently describedtechnology encompasses the subject matter defined by the claimsappending this specification, and any alterations, modifications, orequivalents of those claims.

EXAMPLES Example 1: Chemical Stability of Benzoate and HeteroarylCarboxylate Conjugates of Hydrocodone

Exemplary conjugates of hydrocodone of the present technology andcontrol test conjugates not of the present technology were tested forchemical stability under conditions similar to what a potential drugabuser may use to “extract” the active portion of the molecule, forexample dissolved in water, hydrochloric acid or sodium bicarbonateeither at ambient temperature or 100° C. The conjugates were placed in asolution of water at either ambient temperature (about 20° C.) or in anoil bath at 100° C. for one hour and the amount of the conjugate thatwas hydrolyzed under these conditions was measured. Table 1 demonstratesthe results, showing that the conjugates did not release hydrocodone atambient temperature or when heated in water to 100° C. for one hour.

TABLE 1 water^(a) Compound ambient 100° C. 4-OH-Bz-HC 0% 0% 2-Abz-HC 0%0% 4-MeO-Bz-HC 0% 0%

Further, samples of conjugates of hydrocodone of the present technologywere tested and compared with samples of other conjugates not of thepresent technology of hydrocodone (Adipate-HC) for their hydrolysis tohydrocodone after dilution in 1 N hydrochloric acid (HCl) for 1 hour atambient temperature (˜20° C.) or in an oil bath at 100° C. Thepercentages indicate how much of the initial amount of conjugate washydrolyzed under these conditions. The results are shown in Table 2.

TABLE 2 %-release in 1N HCl^(a) Compound ambient 100° C. 4-OH-Bz-HC 0%30% 2-Abz-HC 0% 16% 3-OH-4-MeO-Bz-HC 0% 35% 2-OH-Bz-HC 3% 27% Adipate-HC13% 100%

Samples of each conjugate were dissolved in a solution of 5% NaHCO₃ forone hour at either ambient temperature (˜20° C.) or in an oil bath at100° C. The percentages indicate how much of the initial amount ofconjugate was hydrolyzed under these conditions as shown in Table 3 forthe conjugates of the present technology and comparison conjugates notof the present technology (Tyr-Tyr-Phe-Phe-Ile-Hydrocodone (YYFFI-HC) orAdipiate-HC).

TABLE 3 %-release in 5% NaHCO₃ ^(a) Compound ambient 100° C. 4-OH-Bz-HC1% 23% 3-OH-4-MeO-Bz-HC 0% 36% YYFFI-HC 0% 70% Adipate-HC 3% 100%

Example 2: Oral PK Profiles of Conjugated Hydrocodone of the PresentTechnology

Oral PK curves were determined for benzoate-hydrocodone (Bz-HC), aprodrug of the present technology, as compared to two conjugates notwithin the scope of the present technology: YYFFI-HC and Diglycolate-HC.Rats were orally administered an amount of the conjugate equivalent to 2mg/kg of freebase hydrocodone and the plasma concentrations of releasedhydrocodone and of the active metabolite hydromorphone were measuredover time by LC-MS/MS. As shown in FIG. 5, the oral PK curves forreleased hydrocodone were somewhat similar for Bz-HC and YYFFI-HC, buthydrocodone plasma concentrations produced by Bz-HC were mostlysignificantly higher than hydrocodone concentrations generated byDiglycolate-HC (AUC and C_(max) for Bz-HC were approximately 40% and 50%higher, respectively). Additionally, Bz-HC created higher plasmaconcentrations of the more potent active metabolite hydromorphone (FIG.6) than both, YYFFI-HC (AUC and C_(max) for hydromorphone released fromBz-HC were approximately 60% and 80% higher, respectively) andDiglycolate-HC (AUC and C_(max) for hydromorphone released from Bz-HCwere approximately 55% and 180% higher, respectively). This suggeststhat all three compounds undergo a different metabolic pathway and thatBz-HC would have pain relieving effects potentially greater than eitherexample.

Example 3: Intranasal PK Profile of Conjugates of Hydrocodone

Conjugates of hydrocodone of the present technology were tested forabuse resistance capabilities by examining the efficiency of ahydrolysis when administered via routes other than oral. Rats wereintranasally treated with conjugate in an amount equivalent to 2 mg/kgof hydrocodone freebase and the concentration of released hydrocodoneand of the active metabolite hydromorphone in the plasma of the rat weremeasured over time by LC-MS/MS. Hydrocodone plasma concentrations weresignificantly lower for Bz-HC (AUC and C_(max) for hydromorphonereleased from Adipate-HC were approximately 280% and 60% higher,respectively) as shown in FIG. 7. Moreover, Bz-HC produced very lowplasma concentration of hydromorphone when compared to Adipate-HC (AUCand C_(max) for hydromorphone released from Adipate-HC wereapproximately 750% and 660% higher, respectively) as shown in FIG. 8.

Prodrugs of the present technology provide hydrocodone and hydromorphoneplasma concentrations that are significantly lower than respectiveplasma concentration for unbound Hydrocodone.BT or for other prodrugclasses when administered intranasally.

Example 4: Exemplary Intravenous PK Profiles of Conjugates of thePresent Technology

The conjugates of hydrocodone of the present technology are hydrophobic,for example, Bz-HC, Nicotinate-HC, 4-MeO-Bz-HC, Piperonylate-HC,4-OH-Bz-HC, Salicylate-HC, 3-OH-4-MeO-Bz-HC, 3-OH-Bz-HC and Gallate-HC.Therefore, these compounds cannot be administered intravenously at oralequivalent doses because they do not dissolve in a practical amount ofwater since injectable compounds must be completely in solution, becauseany solid particle may cause an embolism. The amount of water necessaryto dissolve a desirable amount of conjugate would make an injectionunfeasible and thus the present compositions and prodrugs haveanti-abuse potential as opposed to other hydrocodone conjugates that arewater soluble, such as Adipate-HC and Diglycolate-HC which can beadministered intravenously at oral equivalent doses.

Example 5: Comparison of Oral PK Profiles of Conjugates of Hydrocodone

The plasma concentrations of hydrocodone released from Bz-HC andNicotinate-HC were compared to plasma concentrations of hydrocodonegenerated by unconjugated Hydrocodone.BT after oral administration torats. Rats were treated with conjugate or unconjugated drug in an amountequivalent to 2 mg/kg of hydrocodone freebase and the plasmaconcentration of hydrocodone or hydromorphone was measured by LC-MS/MSas demonstrated in FIGS. 9 and 10 respectively. The oral plasmaconcentration of hydrocodone released from Bz-HC increased similarly tothe hydrocodone plasma concentrations observed with Hydrocodone.BT,until it reached C_(max) (C_(max) was approximately equal for bothcompounds). After T_(max), the hydrocodone plasma concentration forBz-HC decreased in a slower and more controlled fashion than forunconjugated Hydrocodone.BT (FIG. 9 and FIG. 10). Bz-HC had a higher AUC(AUC was approximately 25% higher, FIG. 9) when compared toHydrocodone.BT and similar results were observed for the plasmaconcentrations of the active metabolite hydromorphone (FIG. 10).

Nicotinate-HC, produced hydrocodone and hydromorphone plasmaconcentrations that were below the respective concentrations found forunconjugated Hydrocodone.BT. The corresponding AUC values, however, werewithin the range of bioequivalence for the same dose (based onhydrocodone freebase).

2-ABz-HC demonstrated a different release profile after oraladministration to rats than Bz-HC or the unconjugated drugHydrocodone.BT. Rats were treated with an amount equivalent to 2 mg/kgof hydrocodone freebase and the plasma concentration of hydrocodone orhydromorphone was measured by LC-MS/MS over time as shown in FIG. 11 orFIG. 12 respectively. 2-ABz-HC released hydrocodone very slowlyindicated by a gradual increase of plasma concentration followed by anattenuated decrease (FIG. 11). This resulted in a flattened PK curvewhen compared with Hydrocodone.BT (T_(max) for 2-ABz-HC wasapproximately four times longer, AUC and C_(max) were approximately 35%and 60% lower, respectively). Overall, the PK curve of hydromorphone wasalso flatter for 2-ABz-HC than for Hydrocodone.BT (FIG. 12) but did showa small initial spike (AUC and C_(max) for 2-ABz-HC were approximately25% and 50% lower, respectively).

Example 6: Determination of Variation in Plasma Concentrations ofBenzoate-Hydrocodone

To determine the variability of the plasma concentration of hydrocodone(HC) and hydromorphone (HM), the coefficient of variation (CV) wascalculated for individual animals that were dosed with an amountequivalent to 2 mg/kg of hydrocodone freebase of benzoate-hydrocodone orthe unconjugated hydrocodone bitartrate (BT) and the plasmaconcentrations of hydrocodone and hydromorphone were measured byLC-MS/MS over time. The CV was calculated by dividing the standarddeviation of plasma concentrations in individual animals by the meanplasma concentrations of all dosed animals for a given time point. The“average CV” is the mean CV for all time points, as shown in Table 4.

TABLE 4 Average CV^(a) Compound HC HM Bz-HC 46 41 Hydrocodone•BT 75 64

The lower average CV for Bz-HC indicates that this prodrug has lowerrelative variability in plasma concentrations of hydrocodone andhydromorphone across all dosed animals and time points than theunconjugated drug, hydrocodone bitartrate.

Example 7: Synthesis of Conjugates of Hydrocodone

Synthesis of Benzoate-Hydrocodone Freebase

To a solution of hydrocodone freebase (0.596 g, 1.99 mmol) intetrahydrofuran (25 mL) was added 1 M LiN(SiMe₃)₂ in tetrahydrofuran(5.98 mL). The resulting orange suspension was stirred at ambienttemperatures for 30 min. after which benzoate-succinic ester (1.25 g,5.98 mmol) was added. The resulting mixture was stirred overnight atambient temperatures and was quenched after 18 h by the addition of 100mL saturated ammonium chloride solution which was allowed to stir foranother 2 h. Ethyl acetate (100 mL) was added to the mixture and washedwith saturated ammonium chloride solution (3×100 mL) and water (1×100mL). Organic extracts were dried over anhydrous MgSO₄, solvent wasremoved and residue was taken up in 2-isopropanol (50 mL). Water wasadded until a solid formed. The resulting mixture was chilled, filteredand dried to obtain benzoate-hydrocodone freebase (0.333 g, 0.826 mmol,42% yield) as a dark brown solid. This synthesis is depicted in FIG.13A.

Synthesis of 2-Boc-aminobenzoic Succinate:

2-Boc-aminobenzoic acid (2.56 g, 10.8 mmol) and N-hydroxysuccinimide(1.37 g, 11.88 mmol) were dissolved in 25 mL of THF. DCC (2.45 g, 11.88mmol) was added in one portion. The reaction was stirred overnight. Thesolid was filtered off and rinsed with acetone (2×10 mL). The filtratewas concentrated to dryness and dissolved in 100 mL of acetone. Theresulting precipitate (DCU) was filtered off and the filtrate wasconcentrated to give a solid, which was collected and rinsed withmethanol (3×4 mL) to yield 3.26 g (90%) of white product.

Synthesis of 2-Boc-aminobenzoic Acid Ester Of Hydrocodone:

To hydrocodone freebase (0.449 g, 1.5 mmol) dissolved in 20 mL ofanhydrous THF was added a solution of LiHMDS in THF (1 M, 4.5 mL, 4.5mmol) over 20 min. The mixture was stirred for 30 min. and2-Boc-aminobenzoic succinate (1.50 g, 4.5 mmol) was added in oneportion. The reaction was stirred for 4 hr and subsequently quenchedwith 100 mL of sat. NH₄Cl. The mixture was stirred for 1 hr. andextracted with 200 mL of ethyl acetate. The ethyl acetate layer waswashed with sat. NaHCO₃ (2×80 mL) and 5% brine (80 mL), dried overanhydrous Na₂SO₄ and concentrated. The residue was purified by silicagel column chromatography (7% MeOH/CH₂Cl₂) to give 449 mg (58%) of anamorphous solid.

Synthesis of 2-aminobenzoic Acid Ester of Hydrocodone DihydrochlorideSalt:

2-Boc-aminobenzoic acid ester of hydrocodone (259 mg, 0.5 mmol) wasstirred in 4 mL of 4 N HCl/dioxane for 4 hr. The solvent was evaporatedto dryness and to the residue was added 5 mL of ethyl acetate. The solidwas collected and rinsed with ethyl acetate to give 207 mg (84%) ofproduct.

Synthesis of 2-MOM-salicylic Succinate:

2-MOM-salicylic acid (3.2 g, 17.6 mmol) and N-hydroxysuccinimide (2.23g, 19.36 mmol) were dissolved in 40 mL of THF. DCC (3.99 g, 19.36 mmol)was added in one portion. The reaction was stirred overnight. The solidwas filtered off and rinsed with acetone (2×10 mL). The filtrate wasconcentrated and the residue was recrystallized from 10 mL of methanolto give 2.60 g (53%) of a white solid.

Synthesis of 2-MOM-Salicylic Acid Ester of Hydrocodone:

To hydrocodone freebase (0.449 g, 1.5 mmol) dissolved in 20 mL ofanhydrous THF was added a solution of LiHMDS in THF (1 M, 4.5 mL, 4.5mmol) over 20 min. The mixture was stirred for 30 min. and2-MOM-salicylic succinate (1.26 g, 4.5 mmol) was added in one portion.The reaction was stirred for 4 hr. and subsequently quenched with 100 mLof sat. NH₄Cl. The mixture was stirred for 1 hr. and extracted with 200mL of ethyl acetate. The ethyl acetate layer was washed with sat. NaHCO₃(2×80 mL) and 5% brine (80 mL), dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by silica gel columnchromatography (8% MeOH/CH₂Cl₂) to give 381 mg (58%) of a syrup.

Synthesis of Salicylic Acid Ester of Hydrocodone Hydrochloride Salt:

To 2-MOM-salicylic acid ester of hydrocodone (380 mg, 0.82 mmol) in 12mL of methanol was added 0.5 mL of conc. HCl (12 N). The reaction wasstirred for 6 hr. The solution was concentrated and residual water wasremoved by coevaporating with methanol (5×5 mL). The resulting residuewas dissolved in 1 mL of methanol followed by 20 mL of ethyl acetate.The cloudy mixture was evaporated to about 4 mL. The resulting solid wascollected and rinsed with ethyl acetate to yield 152 mg (41%) ofproduct.

Example 8: Oral PK Profiles of Conjugated Hydrocodone, Hydrocodone, andHydromorphone in Rats

After oral administration of benzoate-hydrocodone (Bz-HC) to rats, PKcurves were determined for intact Bz-HC, hydrocodone, and the activemetabolite hydromorphone. Rats were orally administered an amount of theconjugate equivalent to 2 mg/kg of freebase hydrocodone and the plasmaconcentrations of intact Bz-HC, released hydrocodone, and the activemetabolite, hydromorphone, were measured over time by LC-MS/MS. As shownin FIG. 14, the exposure to intact Bz-HC prodrug was much lower than theexposure to hydrocodone or hydromorphone (the AUC for intact Bz-HC wasapproximately 10% and 3% of the AUC values for hydrocodone andhydromorphone, respectively).

Example 9: Oral PK Profiles of Conjugated Hydrocodone, Hydrocodone, andHydromorphone in Dogs

After oral administration of benzoate-hydrocodone (Bz-HC) orHydrocodone.BT to dogs, PK curves were determined for intact Bz-HC(Bz-HC arm only), hydrocodone, and the active metabolite hydromorphone.Dogs were orally administered an amount of Hydrocodone.BT or theconjugate equivalent to 2 mg/kg of freebase hydrocodone. The plasmaconcentrations of intact Bz-HC, released hydrocodone, and the activemetabolite, hydromorphone, were measured over time by LC-MS/MS.

A comparison of plasma concentrations of hydrocodone released from Bz-HCand Hydrocodone.BT is shown in FIG. 15. Overall, the plasmaconcentrations of hydrocodone generated by both compounds were quitesimilar. The systemic exposure to hydrocodone was somewhat reduced forBz-HC when compared to Hydrocodone.BT (the AUC value of hydrocodone forBz-HC was approximately 72% of the AUC value for Hydrocodone.BT). TheC_(max) value of hydrocodone for Bz-HC was approximately 92% of theC_(max) value for Hydrocodone.BT.

A comparison of the plasma concentrations of the active metabolite,hydromorphone, following oral administration of Bz-HC or Hydrocodone.BTis shown in FIG. 16. Systemic exposure and maximum plasma concentrationsof hydromorphone were similar for both compounds. The AUC and C_(max)values of hydromorphone for Bz-HC were approximately 103% and 109% ofthe respective values for Hydrocodone.BT

A comparison the plasma concentrations of intact Bz-HC and hydrocodonereleased from Bz-HC is shown in FIG. 17. Similar to the results seen inrats, the plasma concentrations of intact Bz-HC prodrug in dogs were lowwhen compared to the plasma concentrations of hydrocodone (the AUC valuefor intact Bz-HC was approximately 10% of the AUC value forhydrocodone).

Example 10: Intravenous PK Profiles of Conjugated Hydrocodone,Hydrocodone, and Hydromorphone in Rats

Bz-HC (0.30 mg/kg) was administered intravenously to rats. Due to itspoor water solubility (or solubility in PBS), 0.30 mg/kg was close tothe maximum dose that could be administered intravenously to rats. PKcurves were determined for intact Bz-HC, hydrocodone, and the activemetabolite hydromorphone. The plasma concentrations of intact Bz-HC,released hydrocodone, and the active metabolite, hydromorphone, weremeasured over time by LC-MS/MS. The resulting PK curves are shown inFIG. 18.

Example 11: Oral PK Profiles of Hydrocodone and Hydromorphone FollowingVarious Dosages of Bz-HC in Rats

Bz-HC was orally administered to rats at dosages of 0.25, 0.50, 1.00,2.00, 3.00, or 4.00 mg/kg. The plasma concentrations of hydrocodone orhydromorphone were measured by LC-MS/MS, as demonstrated in FIGS. 19 and20, respectively. The exposures (AUC) to hydrocodone and hydromorphoneat doses of Bz-HC between 0.25 and 4.00 mg/kg were fairly linear. Therespective C_(max) values, however, were more variable, particularly forhydromorphone. The maximum plasma concentrations of hydromorphone didnot significantly change at doses above 2.00 mg/kg of Bz-HC.

Description of Bioanalytical Methods Used in Examples 12-13

Validated LC/MS/MS methods were used to measure plasma concentrations ofBz-HC, hydrocodone, hydromorphone and acetaminophen (APAP). The lowerlimits of quantitation (LLOQ) for Bz-HC, hydrocodone, hydromorphone, andAPAP in plasma were 25 pg/mL, 250 pg/mL, 25 pg/mL, and 0.025 μg/mL,respectively.

Description of Pharmacokinetic and Statistical Analysis Conducted inExamples 12-13

Actual blood sampling collection times were used in all PK analyses. Perprotocol times were used to calculate mean plasma concentrations forgraphical displays. Pharmacokinetic parameters for hydrocodone,hydromorphone, and APAP were calculated using standard equations fornon-compartmental analysis. Only plasma concentrations that were greaterthan the LLOQs for the respective assays were used in thepharmacokinetic analysis.

Example 12: Bz-HC.HCl/APAP Human Pharmacokinetic Studies

A study was conducted to assess the pharmacokinetics of Bz-HC,hydrocodone and hydromorphone after administration of single oral dosesof Bz-HC.HCl/acetaminophen (APAP) tablets (6.67 mg/325 mg) andhydrocodone bitartrate (HB)/APAP (7.5 mg/325 mg) at three different doselevels (4, 8, and 8 tablets) under fasted conditions.

This was a single-center, randomized, double-blind, active- andplacebo-controlled, and 7-period crossover. After completing anovernight fast (minimum 8 hours), subjects received each of thefollowing 7 treatments according to their randomized treatment sequence:

-   -   A. 12 placebo capsules    -   B. 12 Bz HC.HCl/APAP 6.67 mg/325 mg tablets (over encapsulated)        (80.04 mg Bz HC.HCl/3,900 mg acetaminophen)    -   C. 4 placebo capsules+8 Bz HC.HCl/APAP 6.67 mg/325 mg tablets        (over encapsulated) (53.36 mg HC.HCl/APAP/2,600 mg        acetaminophen)    -   D. 8 placebo capsules+4 Bz HC.HCl/APAP 6.67 mg/325 mg tablets        (over encapsulated) (26.68 mg HC.HCl/APAP/1,300 mg        acetaminophen)    -   E. 12 HB/APAP 7.5 mg/325 mg tablets (over encapsulated) (90 mg        HB/3,900 mg acetaminophen)    -   F. 4 placebo capsules+8 HB/APAP 7.5 mg/325 mg tablets (over        encapsulated) (60 mg HB/2,600 mg acetaminophen)    -   G. 8 placebo capsules+4 HB/APAP 7.5 mg/325 mg tablets (over        encapsulated) (30 mg HB/1,300 mg acetaminophen)

On dosing days blood samples were collected for Bz-HC.HCl, hydrocodone,and hydromorphone analysis at the following sampling times: within 1hour predose and at 0.5, 1, 1.5, 1.75, 2, 3, 4, 6, 8, 10, 12, and 24hour postdose. As shown in FIGS. 21a and 21b , at the low-dose (4tablets, for example) and mid-dose (8 tablets, for example), thecomposition of Bz-HC.HCl/APAP 6.67 mg/325 mg provided a therapeuticallybioequivalent AUC or C_(max) or both for hydrocodone at about lower than53 mg when compared to an equivalent molar amount of unconjugatedhydrocodone. At the high-dose (12 tablets, for example), the compositionof Bz-HC.HCl/APAP 6.67 mg/325 mg exhibited an improved AUC and rate ofrelease of hydrocodone over time when compared to unconjugatedhydrocodone over the same time period. The composition at the high-doseexhibited lower exposure to hydrocodone at about more than 53 mg whencompared to an equivalent molar amount of unconjugated hydrocodone. Thecomposition at the high-dose also exhibited a lower peak exposure(C_(max)) to hydrocodone at about more than 53 mg when compared to anequivalent molar amount of unconjugated hydrocodone.

As shown in FIGS. 22a and 22b , at the low-dose (4 tablets, for example)and mid-dose (8 tablets, for example), the composition of Bz-HC.HCl/APAP6.67 mg/325 mg provided a therapeutically bioequivalent AUC or C_(max)or both for hydromorphone at about lower than 53 mg when compared to anequivalent molar amount of unconjugated hydromorphone. At the high-dose(12 tablets, for example), the composition of Bz-HC.HCl/APAP 6.67 mg/325mg exhibited an improved AUC and rate of release of hydromorphone overtime when compared to unconjugated hydrocodone over the same timeperiod. The composition at the high-dose also exhibited a lower exposureto hydromorphone at about more than 53 mg when compared to an equivalentmolar amount of unconjugated hydrocodone. The composition at thehigh-dose also exhibited lower peak exposure (C_(max)) to hydromorphoneat about more than 53 mg when compared to an equivalent molar amount ofunconjugated hydrocodone.

A summary of the comparative PK data for Bz-HC.HCl/APAP and HB/APAP ispresented in the following Table 5.

Hydrocodone^(a) Hydromorphone^(a) PK Parameter 4 Tablets 8 Tablets 12Tablets 4 Tablets 8 Tablets 12 Tablets C_(max) 96.4% 90.2% 90.8% 88.8%91.2% 87.5% AUC_(last) 98.4% 94.2% 95.8% 92.8% 94.9% 98.8% AUC_(INF)98.2% 94.8% 97.1% 107.0% 99.2% 107.6% AUC_(0-0.5) 96.9% 88.7% 86.1%88.5% 92.0% 86.4% AUC₀₋₁ 96.7% 89.6% 86.9% 88.7% 92.0% 86.9% AUC₀₋₂95.5% 90.7% 89.4% 89.1% 91.4% 89.7% AUC₀₋₄ 94.7% 91.5% 91.9% 89.9% 92.4%93.3% AUC₀₋₈ 95.6% 92.2% 93.3% 90.0% 92.4% 95.0% AUC₀₋₂₄ 98.4% 94.2%95.8% 92.8% 94.9% 98.8% ^(a)Entries represent the percent-ratio of therespective mean PK parameter for Bz-HC•HCl/APAP to the same mean PKparameter for HB/APAP. Percentages <100% indicate a lower value of therespective PK parameter for Bz-HC•HCl/APAP compared to HB/APAP.

Mean peak exposure to hydrocodone was lower with Bz HC.HCl/APAP at themid- and high-dose but similar at the low-dose when compared to HB/APAP(Table 5). The ratio of mean C_(max) values for Bz-HC.HCl/APAP:HB/APAPin terms of hydrocodone exposure was greater than 96% at the low-dose,such as 4 tablets. The ratio of mean C_(max) values forBz-HC.HCl/APAP:HB/APAP in terms of hydrocodone exposure was about 90-91%at the mid- and high-dose, such as 8 and 12 tablets.

Drug users seek fast onset of euphoria for fast reward which plays animportant role in reinforcing behavior and addiction. As a result, loweropioid exposure, particularly in the first 1-2 hours followingadministration, is less desirable by drug users and more desirable forabuse-deterrent opioid therapies. At the mid- and high-dose, the partialareas under the curve for hydrocodone from 0 to 0.5 hours post-dose(AUC_(0-0.5)), from 0 to 1 hour post-dose (AUC₀₋₁), and from 0 to 2hours post-dose (AUC₀₋₂) showed the most significant reduction inexposure with Bz-HC.HCl APAP compared to HB/APAP (Table 5).

Example 13: Effects on Hydrocodone-Induced Respiratory Depression andHypoxia in Recreational Drug Users

The characteristic pattern of opioid-induced respiratory depression is areduced respiratory rate (bradypnea) with deep, sighing ventilations.Patients may often be conscious but lack the drive to breathe. Oncegiven verbal commands to breathe, the patient may comply and takebreaths when instructed to do so. Carbon dioxide (CO₂) retention fromopioid-induced respiratory depression can exacerbate the sedatingeffects of opioids. The loss of central respiratory drive is typical ofopioids, but this feature is difficult to quantify. If respiration isthe maintenance of adequate arterial CO₂ and O₂ tensions, thenrespiratory depression can be defined as the failure to maintain thosearterial CO₂ and O₂ tensions.

Therefore, a primary threshold of respiratory depression may thedevelopment of hypoxemia, the physical condition of having the presenceof an abnormally low level of oxygen in the circulating blood. Hypoxemiacan subsequently result in hypoxia, the physical condition ofinsufficient oxygen supply to the body or regions of the body. Duringclinically significant respiratory depression, reduced oxygen saturationusually occurs in combination with a reduction in ventilatoryperformance, often manifesting as any combination of a reduction inrespiratory rate, reduction in end-tidal volume, reduction in minutevolume, reduction in arterial pH, reduction in O₂.

During the study described above (Example 12) incidence of hypoxia wasrecorded for each treatment (Table 6). One out of sixty-four subjectsand one out of sixty-five subjects experienced hypoxia at the low-dose(4 tablets) with Bz-HC.HCl/APAP and HB/APAP, respectively. At themid-dose (8 tablets), three out of sixty-five subjects receivingBz-HC.HCl/APAP experienced hypoxia compared to nine out sixty fivepatients with HB/APAP. Thirteen out of sixty-five subjects receivingBz-HC.HCl/APAP experienced hypoxia at the high-dose (12 tablets)compared to twenty-one out sixty-seven subjects with HB/APAP. Therefore,there was a lower incidence of hypoxia in subjects treated withBz-HC.HCl/APAP compared to HB/APAP at the mid- and high-dose. In anotherwords, Bz-HC.HCl/APAP has reduced a side effect of respiratorydepression resulting in lower than normal concentration of oxygen inarterial blood of the patient and hypoxia in the patient compared tounconjugated hydrocodone. This reduction was more pronounced at higherdoses (more than 4 tablets, for example) at which hypoxia occurs moreoften and presents a higher safety risk. A summary of the incidence ofhypoxia by treatment is presented in the following Table 6.

4 Tablets 8 Tablets 12 Tablets Bz-HC•HCl/ Bz-HC•HCl/ Bz-HC•HCl/ APAPHB/APAP APAP HB/APAP APAP HB/APAP Total N 64 65 65 65 65 67 Hypoxia 1 13 9 13 21 (N) (1.6%) (1.5%) (4.6%) (13.8%) (20.0%) (31.3%) (%)

In the present specification, use of the singular includes the pluralexcept where specifically indicated.

The presently described technology is now described in such full, clear,concise and exact terms as to enable any person skilled in the art towhich it pertains, to practice the same. It is to be understood that theforegoing describes preferred embodiments of the technology and thatmodifications may be made therein without departing from the spirit orscope of the invention as set forth in the appended claims.

1-14. (canceled)
 15. A method for treating a patient having moderate tosevere pain, narcotic or opioid abuse; or narcotic or opioid withdrawalcomprising administering to the patient a pharmaceutically effectiveamount of a composition of a conjugate of hydrocodone wherein theconjugate exhibits lower mean exposure to hydrocodone about more than 53mg when compared to unconjugated hydrocodone; or has reduced sideeffects when compared with an equivalent molar amount of unconjugatedhydrocodone.
 16. The method of claim 15, wherein the composition is aprodrug.
 17. The method of claim 15, wherein the composition is used toreduce or prevent oral, intranasal or intravenous drug abuse; or toprovide oral, intranasal or parenteral drug abuse resistance.
 18. Themethod of claim 15, wherein the composition exhibits an improved AUC andrate of release of hydrocodone over time when compared to an equivalentmolar amount of unconjugated hydrocodone over the same time period. 19.The method of claim 15, wherein the composition is provided in a dosageform selected from the group consisting of: a tablet, a capsule, acaplet, a suppository, a troche, a lozenge, an oral powder, a solution,an oral film, a thin strip, a slurry, and a suspension.
 20. The methodof claim 15, wherein the composition is provided in an amount sufficientto provide a therapeutically bioequivalent AUC for hydrocodone at aboutlower than 53 mg when compared to an equivalent molar amount ofunconjugated hydrocodone.
 21. The method of claim 15, wherein at leastone composition is provided in an amount sufficient to provide atherapeutically bioequivalent AUC and C_(max) for hydrocodone at aboutlower than 53 mg when compared to an equivalent molar amount ofunconjugated hydrocodone.
 22. The method of claim 15, wherein one of thereduced side effects comprises a lower than normal concentration ofoxygen in arterial blood of the patient.
 23. The method of claim 15,wherein one of the reduced side effects comprises reduced respiratorydepression in the patient.